Clinical efficiency of using selective progesterone receptor modulators in the treatment of symptomatic uterine fibroids

Introduction

Uterine myoma is the main pathology of the female reproductive organs; it reduces the quality of life due to abnormal uterine bleeding, pain syndrome, infertility and miscarriage [1].

A new drug found for the treatment of fibroids is a selective progesterone receptor modulator, ulipristal acetate (UPA). Appearance of UPA on the market allowed providing pathogenetically valid therapy for uterine bleeding associated with uterine myoma [1, 2]. However, a pain symptom often comes to the fore when uterine bleeding is not so profuse. Some patients are afraid to have the uterus removed if the nodules are large or there are several nodules.

Therefore, the aim of this research was to study UPA effectiveness in case of multiple uterine myomas of different sizes.

Materials and Methods

This study included 30 female patients aged from 27 to 49 years with symptomatic uterine myoma. The women were treated with UPA. The average age of the women was 37.63 ± 1.47 years. At the time of the investigation all the patients had a menstruation. The drug was taken for three months (one course of treatment). Before and after the treatment, we assessed the nature of symptoms and their severity as well as myomatous nodes using sonography.

For diagnosing uterine myoma and assessing the nodes, all patients underwent ultrasonography with ultrasound apparatus SonoAce R7 (Samsung Medison, South Korea). Ultrasound examination revealed uterine volume, the size and the volume of nodes before and after the treatment. Ultrasonography was performed with color Doppler mapping and Doppler sonography using multifrequency transabdominal (2.5-3.5-4.0 MHz) and transvaginal (4.0-6.0-8.0 MHz) sensors. The volume of myomatous nodes was calculated by the formula: 0.523 x (ABC), where A is longitudinal, B is anteroposterior, C is transverse dimensions [3].

Uterine bleeding was assessed using the Pictorial blood loss assessment chart (PBAC). Patients completed PBAC daily throughout the course of treatment. Menorrhagia was defined as the number of points on the scale of PBAC more than 100, which corresponded to blood loss of more than 80 ml. Assessment of 100 points according to the PBAC scale was a qualification criterion [4].

The severity of pain syndrome was assessed using the “Visual Analog Scale” (VAS).

The statistical data processing was performed using the platform of Microsoft Excel 2010, Statistica 6.0. The difference in average values was taken as statistically reliable if the value did not exceed 0.05.

Results

The main clinical manifestation was a pain symptom which was observed in 14 patients (46.7%). The combination of pain and heavy menstrual bleeding (HMB) was noted in 11 patients (36.7%). HMB was noted in 3 patients (10%), 2 patients (6.7%) could not get pregnant while having uterine fibroids. Thus, 25 patients (83.3%) experienced a pain symptom and 14 patients (46.7%) had HMB. According to VAS, the pains were evaluated from 4 to 9 points. Along with it, mild pain (3-4 points) was noted in 3 patients (10%), moderate pain (5-6 points) was in 6 patients (20%), severe pain (7-8 points) was in 13 patients (43.3%) and 3 patients (10.0%) assessed the pain as unbearable (9-10 points).

There were 19 women (63.3%) with multiple uterine fibroids and 11 women (36.7%) with a single myomatous node. Dimensions of the nodes and the volume of the dominant node were taken into account. Dimensions of the nodes ranged from 0.66 cm to 9.5 cm; nodes up to 3 cm (0.66 to 2.6 cm) were in 4 women (13.4%), nodes from 3 to 6 cm (3.1 cm to 5.6 cm) were in 13 women (43.3%), nodes from 6 to 10 cm (6.3-9.5cm) were in 13 patients (43.3%). The average size of single myomatous nodes was 5.44 ± 0.89 cm, the average size of the dominant node in multiple fibroids was 5.5 ± 0.68 cm. The volume of a single node and a dominant node in multiple uterine myoma fluctuated from 2.03 to 300 cm3. The average volume of nodes was 105.48 ± 13.48 cm3.

On ultrasound the volume of the uterus body (taking into account the size of the uterus without the size of the nodes) ranged from 65 to 308 cm3, comprising on average 193.5 ± 28.55 cm3.

After completing one course of treatment, all 25 patients continued experiencing the pain. However, intensity of pain decreased from 6 to 4 points due to the absence of patients with unbearable pain (before treatment it was noted in 3 women) and severe pain (there were 13 women before treatment). Intensity of light pain (1-2 points) was not observed in any woman by the end of one course of treatment. Mild pain was noted in 15 women: its intensity remained constant in 3 women, it became decreased in all 6 patients with moderate pain (5-6 points) and 6 patients out of 13 with severe pain. Moderate pain was noted in 10 patients (before treatment there were 6 women) due to the fact that 7 patients had severe pain and 3 patients had unbearable pain.

Thus, by the end of the treatment, no patient assessed the pain as unbearable or severe, while 15 women had moderate pain, and mild pain was observed in 10 patients.

By the 7th day of treatment initiation, uterine bleeding was controlled in 12 out of 14 patients (85.7%) who complained of profuse menstruation; bleeding was considered to be controlled on the day from which the total PBAC score for all subsequent 28-day cycles and till the end of the treatment period did not exceed 75. Amenorrhea was noted in 11 patients (78.5%); amenorrhea was considered to start on the day from which the total score for PBAC for the next 28 days and for all subsequent 28-day cycles and till the end of the treatment period is ≤ 2. It contributed to an increase in the level of hemoglobin and iron (Нв 113.16 ± 3.32g/L) if compared with the initial level of 106.74 ± 4.81g/L. Bleeding was observed in three patients at the time of supposed menstruation, while two women had 20 points according to PBAC and one patient had moderate menstruation which according to PBAC is equal to 80 points, and does not correspond to the amenorrhea criterion.

The volume of the uterus ranged from 65 to 308 cm3 which on average comprised 193 ± 28.55 cm3; after taking the medication for one month the uterine volume became 192.4 ± 44.84 cm3, after two months of the treatment it was 167.7 ± 38.79 cm3, after three months 143.32 ± 23.85 cm3. By the end of the treatment, the decrease in the volume of the uterus reached 26%.

Decrease in the volume of the uterus was noted after the first month of UPA administration, due to the fact that three cases when the volume of the uterus became normal (up to 65 cm3) comprised 10%. Its volume remained the same after a full course of treatment.

Before treatment the uterine volume was twice higher than normal in 16 patients (53.3%), it was 66-132 cm3; after the first month of treatment such uterine volume was observed in 15 cases (50%), after the second month it was in 16 cases (53.3%), and after the third month it was in 15 cases (50%).

A significant decrease occurred in cases of increase in the volume of the uterus by 4 times (199-264 cm3), it was observed before treatment in 3 cases (10%), and after the first month it was not observed in any case, at the end of the second month it was revealed in 2 women (6.7%) and by the end of the course of treatment there were no cases.

The volume of the uterus was five times higher than normal (264-330 сm3) in 6 patients (20%) before treatment, during the second month of treatment it was observed in 5 patients (16.7%), by the end of the second month only one patient (3.3%) had that indicator and it remained the same after the third month (р < 0.05).

The size of the uterus three times higher than the normal (133-198 cm3) was observed in 3 cases (16.7%) before treatment; the number of cases increased due to the fact that the volume of the uterus 4 and 5 times higher decreased by the end of the first month of treatment, there were 7 patients (23.3%); increase up to 8 cases (26.7%) was observed at the end of the second month of treatment, and at the end of the third month increase up to 11 cases (36.7%) was noted, which is significantly higher than before therapy initiation (p < 0.05).

Therefore, the first course of treatment with UPA allowed reducing the volume of the uterus due to reliable decrease in the number of cases of increased uterine volume by 3-5 times.

After a 3-month course of UPA administration, myoma nodes less than 3 cm (1.8 to 2.5 cm) were noted in 13 cases (43.3%) instead of 4 cases (13.4%), 3 to 6 cm (3.1-5.6 cm) in 11 patients (36.7%) instead of 13 patients (43.3%), more than 6 cm (6.3-9.5 cm) were revealed in 6 patients (20.0%) instead of 13 patients (43.3%). Thus, there was a significant decrease in the size of the nodes for more than 6 cm.

One of the indications for surgical treatment is an increase in the uterus for up to 13-14 weeks, the node volume for surgical treatment calculated according to the formula (0.523 x (АBС) is about 100 cm3 [3]. In this regard, the volume of a single node and the dominant one in case of multiple uterine myoma was divided into groups from 2 to 300 cm3: 17 cases (56.7%) ranging from 2.0 to 100 cm3, 7 cases (23.3%) ranging from 101 to 200 cm3, 6 cases (20%) ranging from 201 to 300 cm3.

The number of patients with nodes of up to 100 cm3 volume after the first month of treatment decreased from 17 patients (56.7%) to 16 patients (53.3%); there were cases with nodes less than 2 cm3 (2-6.7%). At the end of the second month, the number of cases with nodes of up to 100 cm3 increased to 19 patients (63.3%); at the end of the third month their number increased to 20 cases (66.7%).

The volume of the dominant node from 101 to 200 cm3 before treatment was revealed in 7 patients (23.3%); after the first month of treatment it was observed in 8 patients (26.7%), after the second and third months of treatment it was in 5 women (16.7%). At the end of the third month of treatment, the number of cases with a node volume from 201 to 300 cm3 was 2 patients (6.6%) versus 6 patients (20%) before treatment. Thus, after one course of treatment the number of cases for which surgical treatment was required decreased from 13 cases (43.3%) to 7 cases (23.3%), i.e. by 1.9 times.

Color Doppler flow ultrasound revealed the presence of a “mosaic” form of mapping, marked blood circulation in myoma nodes along the periphery. In addition, there was a low index of vascular resistance, which ranged from 0.47 to 0.69 m/sec, on average it was 0.54 m/sec. After one course of treatment with UPA, a change in blood flow was observed, resulting in the reduction in the vascular pattern in the color Doppler flow mapping and a “mosaic” form of the blood flow. In addition, an increase in the resistance index was noted, which ranged from 0.65 m/sec to 0.78 m/sec, on average it was 0.70 m/sec. Resistance index increased by 0.16 m/sec. Reduction of mosaic blood flow, increased vascular resistance indicate that UPA leads to a decrease in the number of arteriovenous anastomoses in the nodes and decreased blood flow in them; all these factors result in the reduction in the size and volume of nodes.

Conclusion

The use of UPA led to the reduction of intensity of pain syndrome and menstrual bleeding due to decrease in the volume of myomatous nodes, volume and the size of the uterus and nodes.

After the first course of UPA we noted the decrease in the volume of the uterus which was 3-5 times higher before the treatment (p < 0.05). We also observed reduction in the size of nodes, before the treatment the nodes were more than 6 cm (р < 0.05). Due to this, there was a 1.9-fold decrease in the number of cases of node volume less than 100 cm3. Such changes occurred due to the changes in blood flow in the nodes as a result of drug administration. There was a significant increase in vascular resistance, decreased blood flow, especially mosaic, that indicate a decrease in the number of arteriovenous anastomoses between newly formed vessels.

Thus, one course of UPA treatment reduced the need for surgical intervention in patients with uterine myoma of more than 13-14 weeks, which is an indication for surgical treatment. It has both social and economic significance.